CN111920853B - 素馨花及其提取物在制备治疗高脂血症、代谢综合征或非酒精性脂肪肝病药物中的应用 - Google Patents
素馨花及其提取物在制备治疗高脂血症、代谢综合征或非酒精性脂肪肝病药物中的应用 Download PDFInfo
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Abstract
本发明公开了素馨花及其提取物在制备治疗高脂血症、代谢综合征或非酒精性脂肪肝病药物中的应用，属于医药领域。本发明发现素馨花及其提取物不仅能显著减轻高脂高胆固醇食物引起的肥胖和降低相关的葡萄糖耐量受损，大大降低脂肪含量，还能显著降低高脂高胆固醇喂养的小鼠血清和肝脏中甘油三酯和胆固醇水平，另外，素馨花及其提取物还可以激活胰岛素信号通路中Akt的磷酸化，从而提高胰岛素敏感性。本发明开拓了素馨花及其提取物的药物用途，并为治疗高脂血症、代谢综合征或非酒精性脂肪肝病提供了新的可能。
Description
技术领域
本发明属于医药领域，具体涉及素馨花或其提取物在制备治疗高脂血症、代谢综合征或非酒精性脂肪肝病药物中的应用。
背景技术
代谢综合征是一系列包括2型糖尿病，中心性肥胖，血脂异常和高血压在内的病理状况[1]。中心性肥胖和胰岛素抵抗(靶组织对胰岛素敏感性的能力受损)是代谢综合征发病机制的基础[2]。导致中心性肥胖和胰岛素抵抗的重要饮食因素之一是高脂肪饮食，因为其能量含量和脂肪酸可对胰岛素敏感性产生不同程度的直接作用[1,2]。非酒精性脂肪性肝病(NAFLD)是最为常见慢性肝脏疾病,与肥胖等代谢综合征密切关联[3,4]。
目前，世界代谢综合征发病率大约为20-25％，患者超过2亿。随着肥胖等代谢综合征患率的进一步上升,NAFLD对于整个社会带来的经济负担和压力也日渐突出。NAFLD病程由轻而重，从单纯性脂肪肝向脂肪性肝炎，甚至肝硬化以及肝细胞癌症发展[5]。在美国，约25％成人患有脂肪肝,其中25％NAFLD发展成非酒精性脂肪性肝炎(NASH)[6],在我国约15％成人患有NAFLD[7]。
单纯性脂肪肝是指脂质在肝脏的过度蓄积，尽管它本身的危害相对较小而且可逆,但是NASH存在肝损伤,是向不可逆性的严重肝脏疾病(包括肝纤维化,肝硬化和肝癌)转变的关键阶段[8,9]。因此，对NASH的治疗尤为重要。仅在美国，NASH所直接产生的医疗费用估计高达1000亿美元，其中大部分是由脂肪性肝炎及其后遗症所引起的[10]。近年来，NASH危害性受到越来越多的关注，尽管在过去数年中增加了代谢综合征和NASH的治疗方法和数量，但它们都存在限制治疗的副作用[6,11-13]。因此，对于代谢综合征和NASH的治疗，仍需要具有改善的功效和更少的副作用的巨大的医学和新药开发。
素馨花(Jasminum grandiflorum Linn.)为木犀科茉莉属的药食两用植物，已记载于《全国中草药汇编》和《中药大辞典》，味苦、性平、肝经，具有“舒肝解郁、行气止痛”之功效。现代药理学发现，素馨花具有良好的抗炎、抗氧化、抗菌、降糖等多种生物活性，是最常用的民间中药材之一[14-17]。但关于素馨花对降脂方面活性的影响尚不清楚。
发明内容
为解决上述现有技术中存在的缺点和不足，本发明的目的在于提供一种素馨花或其提取物的新用途，以将素馨花或素馨花提取物用于制备治疗高脂血症、代谢综合征或非酒精性脂肪肝病的药物中。
为了达到上述目的，第一方面，本发明提供了一种素馨花或其提取物的应用，以将素馨花或素馨花提取物用于制备治疗高脂血症、代谢综合征、非酒精性脂肪肝病中至少一种病症的药物。
素馨花及其提取物不仅能显著减轻高脂高胆固醇食物引起的肥胖和降低相关的葡萄糖耐量受损，大大降低脂肪含量，还能显著降低高脂高胆固醇喂养的小鼠中血清和肝脏中甘油三酯和胆固醇水平，另外，素馨花及其不同提取物还可以激活胰岛素信号通路中Akt的磷酸化，从而提高胰岛素敏感性。这些说明素馨花及其提取物具有治疗高脂血症、代谢综合征、非酒精性脂肪肝病的功能。
作为本发明应用的优选实施方式，所述素馨花提取物由素馨花经有机溶剂或有机溶剂与水的混合溶剂提取所得。
作为本发明应用的优选实施方式，所述有机溶剂为乙酸乙酯、乙醇、正丁醇中的至少一种。
作为本发明应用的优选实施方式，所述有机溶剂为乙酸乙酯、乙醇中的至少一种。采用乙酸乙酯、乙醇或乙醇水溶液提取得到的素馨花提取物能更加显著地减轻高脂高胆固醇食物引起的肥胖和降低相关的葡萄糖耐量受损，对血清中胆固醇含量、肝脏中甘油三酯和胆固醇含量的降低作用也更明显。
作为本发明应用的优选实施方式，所述素馨花提取物的制备方法包括以下步骤：将素馨花采用乙醇或乙醇水溶液进行提取，收集提取液，浓缩去除乙醇，得到乙醇提取物，即得所述素馨花提取物。服用乙醇提取物，即使在食用高脂高胆固醇饲料时，也会使小鼠的体重负增长，并能明显降低血糖、血清胆固醇和肝脏胆固醇，明显激活胰岛素信号通路中Akt的磷酸化。
作为本发明应用的优选实施方式，所述素馨花提取物的制备方法包括以下步骤：先将素馨花采用乙醇或乙醇水溶液进行提取，收集提取液，浓缩去除乙醇，得到乙醇提取物，再将所述乙醇提取物溶于水中，得到混悬液，采用乙酸乙酯对所述混悬液进行萃取，收集乙酸乙酯层萃取液，浓缩干燥，得到乙酸乙酯萃取物，即得所述素馨花提取物。相比乙醇提取物，乙酸乙酯萃取物在降低全身脂肪、血糖、血清甘油三酯、肝脏甘油三酯、肝脏胆固醇等方面的效果更好。
第二方面，本发明提供了一种治疗高脂血症、代谢综合征、非酒精性脂肪肝病中至少一种病症的药物，所述药物包括素馨花、素馨花提取物中的至少一种。
作为本发明药物的优选实施方式，所述素馨花提取物由素馨花经有机溶剂或有机溶剂与水的混合溶剂提取所得。
作为本发明药物的优选实施方式，所述有机溶剂为乙酸乙酯、乙醇、正丁醇中的至少一种。
作为本发明药物的优选实施方式，所述有机溶剂为乙酸乙酯、乙醇中的至少一种。
作为本发明药物的优选实施方式，所述素馨花提取物的制备方法包括以下步骤：将素馨花采用乙醇或乙醇水溶液进行提取，收集提取液，浓缩去除乙醇，得到乙醇提取物，即得所述素馨花提取物。
作为本发明药物的优选实施方式，所述素馨花提取物的制备方法包括以下步骤：先将素馨花采用乙醇或乙醇水溶液进行提取，收集提取液，浓缩去除乙醇，得到乙醇提取物，再将所述乙醇提取物溶于水中，得到混悬液，采用乙酸乙酯对所述混悬液进行萃取，收集乙酸乙酯层萃取液，浓缩干燥，得到乙酸乙酯萃取物，即得所述素馨花提取物。
与现有技术相比，本发明具有如下优点：素馨花及其提取物对高脂血症、代谢综合征和非酒精性脂肪肝病具有治疗作用，尤其是素馨花及其乙酸乙酯提取物和乙醇提取物，作用更明显。
附图说明
图1为素馨花及其不同溶剂提取物对小鼠体重及脂肪含量的影响，其中(A)治疗前小鼠体重，(B)治疗16天后小鼠体重增加量，(C)和(D)分别为在治疗第12天采用MRI体脂分析系统测得的小鼠全身非脂肪重量以及全身脂肪重量，(E)和(F)分别为治疗16天后小鼠附睾脂肪组织重量以及小鼠附睾脂肪组织重量与体重的比值；
图2为素馨花及其不同溶剂提取物对小鼠葡萄糖耐量的影响，其中(A)空腹血糖水平，纵坐标单位mM，(B)注射葡萄糖后血糖水平随时间变化的趋势图，纵坐标单位mM，(C)ipGTT期间血糖水平曲线下的面积(AUC)，纵坐标单位mM×120分钟，(D)ipGTT期间血糖水平曲线下的面积增量(iAUC)，纵坐标单位mM×120分钟；
图3为素馨花及其不同溶剂提取物对小鼠体内甘油三酯和胆固醇水平的影响，其中(A)血清中甘油三酯的含量，纵坐标单位mM，(B)血清中胆固醇的含量，纵坐标单位mg/mL，(C)肝脏组织中甘油三酯的含量，纵坐标单位μmol/g，(D)肝脏组织中胆固醇的含量，纵坐标单位mg/g；
图4为素馨花及其不同溶剂提取物对小鼠胰岛素信号通路的影响，其中(A)-(D)为肝脏组织中磷酸化Akt和总Akt水平数据，(A)磷酸化Akt与GAPDH比值，(B)总Akt与GAPDH比值，(C)磷酸化Akt与总Akt的比值，(D)免疫印迹的代表性图像，(E)-(H)为肌肉组织中磷酸化Akt和总Akt水平数据，(E)磷酸化Akt与GAPDH比值，(F)总Akt与GAPDH比值，(G)磷酸化Akt与总Akt的比值，(H)免疫印迹的代表性图像。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
1、实验方法
(1)素馨花提取物的制备
素馨花乙醇提取物的制备：称量适量干燥素馨花，粉碎后加入体积分数95％乙醇，于80℃水浴锅中进行提取，每次提取2h，每次提取后过滤并收集提取液，共提取3次，合并提取液，用旋转蒸发仪浓缩至无醇味，得到乙醇提取物。
素馨花乙酸乙酯萃取物的制备：将上述乙醇提取物用蒸馏水溶解成混悬液，然后加入适量乙酸乙酯溶剂进行萃取，静置后进行分层，收集乙酸乙酯层萃取液，重复萃取2-3次，合并乙酸乙酯层萃取液，用旋转蒸发仪浓缩至干，得到乙酸乙酯萃取物。
素馨花正丁醇萃取物的制备：将上述萃取过程产生的残余水层继续加入适量水饱和的正丁醇溶剂进行萃取，静置后进行分层，收集正丁醇层萃取液，重复萃取2-3次，合并正丁醇层萃取液，用旋转蒸发仪浓缩至干，得到正丁醇萃取物。
(2)动物分组治疗
将9-10周龄雄性C57BL/6J小鼠(体重22.0-24.0g)适应两周后，随机分为6组，分别为正常普食对照组(CH-Con)、高脂高胆固醇模型组(HFHC-Con)、高脂高胆固醇素馨花治疗组(HFHC-R)、高脂高胆固醇素馨花乙酸乙酯萃取物治疗组(HFHC-A)、高脂高胆固醇素馨花乙醇提取物治疗组(HFHC-B)、高脂高胆固醇素馨花正丁醇萃取物治疗组(HFHC-C)。CH-Con组每天喂养正常的普通饲料，HFHC-Con组每天喂养HFHC饲料，HFHC-R、HFHC-A、HFHC-B和HFHC-C组每天喂养混有素馨花或其提取物(即乙醇提取物、乙酸乙酯萃取物或正丁醇萃取物)的HFHC饲料，各组饲料喂养量相同，其中HFHC-R组每天食用素馨花的剂量为2g/kg，HFHC-A、HFHC-B和HFHC-C组每天食用相应素馨花提取物的剂量为500mg/kg，各组分别喂养16天，每1-2天记录小鼠体重和食物摄入量。在实验结束时，通过颈脱位法处死小鼠，收集附睾脂肪并使用分析天平称重，冷冻钳收集肝脏(LIV)和肌肉(MUS)组织进行进一步评估。所有的小鼠均在标准的实验室条件下饲养，温度22±1℃，昼夜12小时交替。
(3)小鼠总体脂肪含量的测定
在上述各组小鼠试验治疗的第12天，使用Echo MRI国际医疗设备公司的EchoMRITM-100H分析仪(EchoMRI)评估小鼠体内的总体脂肪含量。在这种无害且非侵入性的实验分析过程中，小鼠被约束在仪器配置的管内。使用EchoMRITM-100H测量全身脂肪组成的原理是基于磁共振成像(MRI)技术。该技术可扫描活体组成，例如脂肪组织、瘦肉组织和游离液。
(4)小鼠葡萄糖耐量测定
在上述各组小鼠试验治疗的第12天，禁食5-6小时后，对小鼠进行腹腔内注射葡萄糖耐量试验(ipGTT)。腹腔注射葡萄糖剂量为2.5g/kg体重(体重参照CH-Con组的平均体重)，并使用Accu-Check血糖仪(Roche Diagnostics GmbH公司)在葡萄糖注射0、15、30、60、90和120分钟后测量血糖水平。
(5)血清甘油三酯和胆固醇水平的测定
在上述各组小鼠试验治疗的第12天，使用肝素毛细管从小鼠尾尖收集50微升血液样本，以防止凝血和溶血。将血样置于装有等体积50微升无菌生理盐水的1.5mL微量离心管中，然后放入冰中。收集完成后立即将样品以15,000rpm速度离心1分钟以分离血清，然后将其转移到干净的eppendorf管(微量离心管)中并在-80℃条件下保存直至使用。
血清中甘油三酯的含量根据试剂盒说明书(Roche Diagnostics GmbH公司)使用Peridochrom TG GPO-PAP试剂，最后通过比色分析进行测定。具体为：将5μL血清样品添加到300μL甘油三酯试剂中，然后在37℃下孵育10分钟，再使用Polarstar Optima酶标仪(德国BMG Lab Technologies)在485nm处测量吸光度。甘油标准品的各种稀释液(0μg/孔-1.050μg/孔)作为内部标准品用于绘制标准曲线。
血清中胆固醇水平根据试剂盒说明书通过酶试剂盒(Roche DiagnosticsGmbH公司，#11491458-216)确定。具体为：将10μL血清样品添加到200μL胆固醇试剂中，然后在37℃下孵育10分钟，再使用Polarstar Optima酶标仪(德国BMG Lab Technologies)在485nm处测量吸光度。胆固醇标准品的各种稀释液(0mg/mL-1.0mg/mL)作为内部标准品用于绘制标准曲线。
(6)肝脏甘油三酯和胆固醇含量的测定
在上述各组小鼠试验治疗的第16天，通过颈脱位法处死小鼠，并立即将肝脏进行冷冻以进行甘油三酯和胆固醇测定。简而言之，使用玻璃杵组织研磨机在氯仿/甲醇(二者体积比2：1)中匀浆肝脏样品(30-40mg)，再将匀浆在室温下于旋转器上孵育过夜，以溶解组织脂质。第二天，添加2mL 0.6wt％的NaCl，然后将样品以2000rpm速度离心10分钟，收集含有溶解的脂质的底层有机相，并在45℃空气中干燥，然后将脂质悬浮在100％乙醇中，并分别按照试剂盒说明书使用Peridochrom TG GPO-PAP试剂(Roche Diagnostics GmbH公司)和酶试剂盒(Roche Diagnostics GmbH公司，#11491458-216)通过比色测定法测定肝脏甘油三酯和胆固醇含量。
(7)蛋白质印迹法
在上述各组小鼠试验治疗的第16天，收集组织之前，腹腔注射胰岛素(0.75IU/kg体重，体重参照CH-Con组的平均体重)刺激20分钟，然后立即冷冻组织并在-80℃条件下保存。通过蛋白质印迹法检测胰岛素信号通路中磷酸化和总Akt的蛋白表达情况。具体操作如下：取各组肝脏(30-40mg)和肌肉(～40mg)用PIPA裂解缓冲液提取蛋白，蛋白浓度通过BCA法定量并调平，样品蛋白(50μg)通过聚丙烯酰胺凝胶电泳分离，然后转印至硝酸纤维素(PVDF)膜上，将PVDF膜在含3wt％BSA的TBST缓冲液中封闭，并与一抗体(1：1000稀释度)在4℃下孵育过夜；第二天，PVDF膜在PBS缓冲液中漂洗后与二抗(1：1000稀释度)室温振荡孵育2小时，最后用增强的化学发光试剂检测蛋白水平。蛋白质印迹法结果用凝胶图像分析软件Image Lab进行分析。
(8)统计学分析
采用Excel和Prism进行数据整理和统计学分析。数据以平均值±标准误表示(n＝3-8，n为每组样品数)。组间差异分析采用t检验方法。以p≤0.05为差异有统计学意义。图1-图4中，HFHC-Con组和CH-Con组进行对比，
表示p<0.01，
表示0.01≤p<0.05；HFHC-A、HFHC-B和HFHC-C组分别和HFHC-Con组进行对比，**表示p<0.01，*表示0.01≤p<0.05。
2、实验结果
(1)素馨花及其不同溶剂提取物对小鼠体重及脂肪含量的影响
各组间小鼠实验前体重没有显著性差异(图1A)。实验结束时，与CH-Con相比，HFHC-Con组小鼠体重明显增加(p<0.01，图1B)，而与HFHC-Con相比，HFHC-R、HFHC-A和HFHC-B组小鼠体重增加明显减少(均为p<0.05，图1B)。
MRI体脂分析结果显示，各组间小鼠全身非脂肪重量没有显著性差别(图1C)。与CH-Con组相比，HFHC-Con组小鼠经MRI扫描全身脂肪含量没有明显增加。与HFHC-Con组相比，治疗组HFHC-R和HFHC-A的小鼠全身脂肪含量明显降低(p<0.05，图1D)。
解剖称重结果亦表明，HFHC-Con组的小鼠附睾脂肪组织重量明显增加(p<0.05，图1E-F)。与HFHC-Con相比，治疗组HFHC-R的小鼠脂肪组织重量显著降低(p<0.05，图1C)，并保持与CH-con组小鼠相似的水平；治疗组HFHC-A的小鼠脂肪含量有所降低(p＝0.06,图1C)。
结果表明，素馨花和其乙酸乙酯萃取物可以显著减轻HFHC食物引起的肥胖，并大大降低了脂肪含量。
(2)素馨花及其不同溶剂提取物对HFHC喂养的肥胖胰岛素抵抗小鼠葡萄糖耐量的影响
为了评估素馨花及其不同溶剂提取物对葡萄糖稳态的作用，对小鼠进行了ipGTT实验。如图2所示，这些提取物在不同程度上降低了HFHC饲养小鼠的空腹血糖和葡萄糖耐受性。与CH-Con组相比，HFHC-Con组小鼠的空腹血糖水平显著升高(p<0.05)；与HFHC-Con组相比，各治疗组小鼠的空腹血糖水平显著降低(p<0.05，图2A)。与HFHC-Con组相比，治疗组HFHC-A小鼠在整个ipGTT期间显示出明显更低的血糖水平，计算出的GTT期间血糖水平曲线下的面积(AUC)(C)和增量面积(iAUC)分别降低了～40％和～60％(图2B-D)。
结果表明，素馨花及其提取物都可以提高HFHC喂养小鼠的葡萄糖耐受性，其中素馨花乙酸乙酯提取物的作用效果非常好，可显著提高HFHC喂养小鼠的葡萄糖耐受性。素馨花及其提取物能通过改善葡萄糖的处理来减轻HFHC饮食诱导的胰岛素抵抗。
(3)素馨花及其不同溶剂提取物对甘油三酯和胆固醇水平的影响
胰岛素抵抗与胰岛素靶组织中的异位脂质蓄积密切相关[18]，因此，我们检测了甘油三酯和胆固醇的水平，以研究素馨花及其不同溶剂提取物对肝脏脂质积累的影响。这些提取物在不同程度上降低HFHC饲养小鼠血浆和肝脏组织的甘油三酯和胆固醇含量(图3)。与CH-Con组相比，HFHC-Con组的血清和肝脏甘油三酯水平并没有显著升高，但与HFHC-Con组相比，治疗组HFHC-A的血清和肝脏甘油三酯水平都明显降低(图3A和C)，治疗组HFHC-R仅有肝脏中甘油三酯水平显著降低(p<0.01，图3C)。
与CH-Con组相比，HFHC-Con组血清和肝脏胆固醇水平显著升高(p<0.01，图3B和D)。与HFHC-Con组相比，各治疗组均显著降低了血清或肝脏胆固醇水平(图3B和D)。
结果表明，素馨花及其不同溶剂提取物都能够降低HFHC喂养的小鼠中甘油三酯和胆固醇水平，表明其对肝脂肪变性(脂肪肝)的功效。
(4)素馨花不同溶剂提取物对胰岛素信号通路的影响
为了进一步检测素馨花不同溶剂提取物对胰岛素信号通路的影响，提取组织之前小鼠被注射了胰岛素。在肝脏组织中，与CH-Con组相比，HFHC-Con组明显抑制了胰岛素刺激的Akt的磷酸化(图4C)。与HFHC-Con组相比，治疗组HFHC-R和HFHC-B显著升高了胰岛素刺激的Akt的磷酸化(p<0.05，图4C)。
在肌肉组织中，与CH-Con组相比，HFHC-Con组显著抑制了胰岛素刺激的Akt的磷酸化(p<0.01，图4F)。与HFHC-Con组相比，各治疗组均升高了胰岛素刺激的Akt的磷酸化，其中HFHC-A和HFHC-B更加显著(p<0.05，图4F)。
结果表明，素馨花提取物可以激活胰岛素信号通路中Akt的磷酸化，从而提高胰岛素敏感性，改善代谢综合征和脂肪肝。
综上，我们认为素馨花及其乙酸乙酯萃取物和乙醇提取物对高脂血症、代谢综合征和非酒精性脂肪具有治疗作用。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
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Claims (1)
1.一种素馨花提取物的应用，其特征在于，所述应用为将素馨花提取物用于制备治疗代谢综合征、非酒精性脂肪肝病中至少一种病症的药物，所述素馨花提取物的制备方法包括以下步骤：先将素馨花采用乙醇或体积分数95％乙醇水溶液进行提取，收集提取液，浓缩去除乙醇，得到乙醇提取物，再将所述乙醇提取物溶于水中，得到混悬液，采用乙酸乙酯对所述混悬液进行萃取，收集乙酸乙酯层萃取液，浓缩干燥，得到乙酸乙酯萃取物，即得所述素馨花提取物。
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